CN1505628A

CN1505628A - Triazole compounds useful in treating diseases associated with unwanted cytokine activity

Info

Publication number: CN1505628A
Application number: CNA028090667A
Authority: CN
Inventors: Js; J·S·塔利斯; J·C·范伦斯; M·P·克拉克; B·E·布拉斯; �ɳ��; M·G·纳彻斯; B·德
Original assignee: Procter and Gamble Ltd
Current assignee: Procter and Gamble Ltd
Priority date: 2001-04-30
Filing date: 2002-04-25
Publication date: 2004-06-16
Also published as: EP1392681A1; US6787555B2; PE20021059A1; JP2004532235A; WO2002088113A1; CA2444500A1; AU2002338522B2; US20030100558A1

Abstract

The present invention relates to 4-aryl triazoles having the formula: (I) wherein R1 is independently selected from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lower heteroalkenyl, lower heteroalkynyl, heterocycloalkyl, heteroaryl, halo, CN, OR4, SR4, S(O)R4, S(O)2R4, and NR4R5; and Q is has the general formula: (II) or (III) said compounds are useful in treating diseases associated with unwanted cytokine activity, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells.

Description

Triazole compounds useful for treating diseases caused by unwanted cytokine activity

Technical Field

The present invention relates to certain triazole compounds that inhibit the release of inflammatory cytokines, such as interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF), from cells. Thus, the compounds of the present invention are effective in treating diseases caused by excessive cytokine activity.

Background

Many cytokine-induced diseases and conditions are associated with excessive or irregular production or activity of one or more cytokines, such as interleukin 1(IL-1), Tumor Necrosis Factor (TNF), interleukin 6(IL-6), and interleukin 8 (IL-8). IL-1 and TNF are important pro-inflammatory cytokines that, together with several other related molecules, mediate the response of inflammatory cells in a variety of diseases and conditions. Pro-inflammatory cytokines such as IL-1 and TNF stimulate other inflammatory mediators such as nitric oxide, cyclooxygenase-2, matrix metalloproteinases. Inhibition of these cytokines can therefore be beneficial in controlling, reducing and alleviating many of these conditions, both directly and indirectly.

High levels of pro-inflammatory cytokines are implicated in a number of diseases, including rheumatoid arthritis (Dinarello, C.A. et al, 1984, Rev. infection. disease 6: 51; Maini, R.E.1999, The Lancet 354: 1932; Weinblatt, M.E.1999, New Eng.J.Med.340: 253), osteoarthritis (Pelletier and Pelletier 1989, J.Rheum.16: 19; Pelletier et al, 1993, am.J.Path.142: 95; Farahat et al, 1993, an Ann.Rheum.Dis.52: 870; Tiku et al, 1992, Cell. 140: 1; Webb et al, 1997, ImO. & C.427: 427; British et al, Zecott et al, 2000, O & C.8: 213), inflammatory response of Escherichia coli, E.35: 35, inflammatory disease (E.35: 35; inflammatory response of diabetes mellitus, Klaus.35: 35; inflammatory disease, Klaus. E.35: 35; inflammatory response, Klaus.35: 35; inflammatory response, Klaus; E.H.35: 35; inflammatory disease, E.35: 35; E.H.); congestive heart failure, Han et al, 2000, Trends cardiovasc. med.10: 19; hunter et al, 1999, n.engl.j.med.341: 1276; behr et al, 2000, circ.102: II-289; shimamoto et al, 2000, Circ: 102: II-289; aukrust et al, 1999, am.J. Cardiol.83: 376, hypertension (Singh et al, 1996 J.Hypertension 9: 867), chronic lung dysfunction, septic shock syndrome (Dinarello, C.A.1995, Nutrition 11:492), tuberculosis, adult dyspnea, asthma (Renzetti et al, Inflammation Res.46: S143), atherosclerosis (Elhage et al, 1998, Circulation 97:242), muscle degeneration, periodontal disease (Howell 1995, Oral Dis.1:266), cachexia, Laplace syndrome, gout, acute synovitis, eating disorders including anorexia nervosa and bulimia nervosa (Holden et al, 1996, Med.Hypothesis 47:423), fever, malaise, myalgia and headache (Beisel am. J.Clin.62: 813). Thus, inhibition of pro-inflammatory cytokine production has the opportunity to treat or prevent many diseases and conditions involving increased levels of pro-inflammatory cytokines.

Inhibitors of the production of numerous small molecule cytokines have been disclosed. (see Salituro, F.G. et al, 1999, 6, pages 807 to 823 and citations therein). In particular, 1, 2, 4-triazoles (WO00/10563 and WO 97/47618), isoxazoles (WO 01/12621) and imidazoles (WO 00/26209, WO99/03837 and the references cited therein) have been disclosed. However, some hepatotoxicity, such as increased liver volume and enhanced cytochrome P450 response, have been reported recently (Foster, M.L. et al, Drug News Perspectrum, 2000, 13(8), 488-. In view of this potential toxicity and the risks associated with developing human medicine, there is a continuing need for potent, novel small molecule cytokine production inhibitors with improved pharmacokinetic and safety profiles.

Summary of The Invention

The present invention provides potent cytokine inhibitors and compounds that are effective in treating conditions caused by excessive activity of these enzymes. In particular, the present invention relates to compounds having the structure of formula (I):

wherein R is¹M, A, a, B, B and Q are defined herein.

The invention also includes optical isomers, diastereomers and enantiomers of the above structures, and pharmaceutically acceptable salts thereof.

The compounds of the invention are useful in the treatment of diseases and conditions characterized by excessive cytokine activity. Accordingly, the invention also provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treating diseases and conditions caused by excessive cytokine activity using these compounds or compositions comprising these compounds.

All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

Detailed Description

The present invention relates to a novel group of compounds which are potent cytokine inhibitors and which are effective in the treatment of conditions characterized by excessive activity of these enzymes.

Terms and definitions

"alkenyl" means a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms, and at least one (preferably only one) carbon-carbon double bond. The alkenyl group may be linear or branched. Preferred branched alkenyl groups have one or two branches, preferably one branch. The alkenyl group may be unsubstituted or have 1 to 4 substituents. Preferred substituted alkenyl groups have 1 to 3 substituents, unless otherwise indicated. Substituents for alkenyl groups include halogen, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkenyl substituents include halogen, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term "lower alkenyl" refers to alkenyl groups having 2 to 6, preferably 2 to 4, carbon atoms.

"alkyl" means a monovalent saturated hydrocarbon chain having 1 to 18, preferably 1 to 12, more preferably 1 to 6 carbon atoms. The alkyl group may be linear or branched. Preferred branched alkyl groups have one or two branches, preferably one branch. The alkyl group may be unsubstituted or have 1 to 4 substituents. Unless otherwise indicated, substituted alkyl groups preferably have 1 to 3 substituents. Substituents for alkyl groups include halogen, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred alkyl substituents include halogen, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term "lower alkyl" refers to an alkyl group having 1 to 6, preferably 1 to 4, carbon atoms.

"alkoxy" refers to the group-OR, where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, OR heterocycloalkyl. Preferred alkoxy groups include methoxy, ethoxy and isopropoxy.

"alkynyl" refers to a monovalent hydrocarbon chain having 2 to 18 carbon atoms, preferably 2 to 12, more preferably 2 to 6 carbon atoms, and having at least one (preferably only one) carbon-carbon triple bond. The alkynyl group may be linear or branched. Preferably, the branched alkynyl group has one or two branches, preferably one branch. Alkynyl groups may be unsubstituted or substituted with 1 to 4 substituents. Unless otherwise indicated, preferred substituted alkynyl groups have 1 to 3 substituents. Substituents for alkynyl groups include halogen, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, thioalkoxy, thioaryloxy, amino, keto, thioketo, nitro, and cyano. Preferred substituents for alkynyl groups include halo, OH, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto groups. The term "lower alkynyl" refers to alkynyl groups having 2 to 6, preferably 2 to 4, carbon atoms.

"amino" means-N (R)₂Wherein each R is independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl. Preferred amino groups include NH₂、NHCH₃And NHC (O) CH₃。

"aryl" refers to an aromatic hydrocarbon ring. The aromatic ring may be a monocyclic ring system or a fused bicyclic ring system. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl ring also refers to phenyl ring. The bicyclic aromatic ring contains from 8 to 12 carbon atoms, preferably from 8 to 10 carbon atoms, more preferably 10 carbon atoms in the ring. Bicyclic aromatic rings include ring systems in which both rings are aromatic or only one ring is aromatic. Preferred bicyclic aryl rings include 5-, 6-, or 7-membered rings fused to a 5-, 6-, or 7-membered ring. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aromatic ring is phenyl. The aromatic ring may be unsubstituted or have 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents on the ring. Preferably, the aromatic ring is unsubstituted or substituted with 1 or 2 substituents. The aromatic ring may be substituted with: halogen, cyano, nitro, hydroxy, amino, alkyl, lower alkenyl, lower alkynyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy [ which means (-OCH)₂O-) radical]Thioalkoxy, thioaryloxy, or any combination thereof. Preferred aryl ring substituents include halogen, cyano, amino, alkyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy.

"aryloxy" refers to the group-OR, where R is aryl OR heteroaryl. Preferred aryloxy groups include phenoxy and pyridyloxy.

"cyano" refers to the group-CN.

"cycloalkyl" is a saturated hydrocarbon ring. Cycloalkyl rings are monocyclic, or are fused, spiro or bridged bicyclic ring systems. Preferably the cycloalkyl ring is monocyclic. Monocyclic cycloalkyl rings contain 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 3, 5 or 6 carbon atoms in the ring. The bicycloalkyl group contains from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicycloalkyl rings include 5-, 6-or 7-membered rings fused to a 5-, 6-or 7-membered ring. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl ring may be unsubstituted or may be substituted on the ring with 1 to 4 substituents. Cycloalkyl substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, heterocycloalkyl, halogen, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred cycloalkyl substituents include halogen, hydroxy, alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, amino, and keto. More preferred cycloalkyl substituents include hydroxy, alkyl and alkoxy.

"cycloalkenyl" is an unsaturated hydrocarbon ring. The cycloalkenyl ring is not an aromatic ring and contains at least one, preferably only one, carbon-carbon double bond. Cycloalkenyl groups are monocyclic or fused, spiro or bridged bicyclic ring systems. Preferred cycloalkenyl rings are monocyclic. Monocyclic alkenyl groups contain 5 to 10 carbon atoms, preferably 5 to 7, more preferably 5 or 6 carbon atoms in the ring. Bicyclic alkenyl groups contain 8 to 12 carbon atoms in the ring. Preferred bicycloalkenyl radicals include 5-, 6-or 7-membered rings fused to a 5-, 6-or 7-membered ring. The ring of a cycloalkenyl group can be unsubstituted or substituted on the ring with 1 to 4 substituents. Substituents for cycloalkenyl groups include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, heterocycloalkyl, halogen, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred cycloalkenyl substituents include halo, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. More preferred cycloalkenyl substituents include OH, alkyl, alkoxy, and keto groups.

"halo" or "halogen" refers to fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine, chlorine and bromine. More preferred halogens are chlorine and fluorine, especially fluorine.

"heteroalkenyl" refers to a monovalent chain having from 3 to 18 member atoms (carbon and heteroatoms), preferably from 3 to 12, more preferably from 3 to 6 member atoms in the chain, and having at least one (preferably only one) carbon-carbon double bond. The heteroalkenyl chain has at least one heteroatom. Heteroalkenyl groups may be straight-chain or branched. Preferred branched heteroalkenyl groups have one or two branches, preferably one branch. Heteroalkenyl groups may be unsubstituted or substituted with 1 to 4 substituents. Preferred substituted heteroalkenyl groups have 1 to 3 substituents, unless otherwise indicated. Substituents for heteroalkenyl groups include halogen, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkenyl substituents include halo, hydroxy, alkyl, alkoxy, aryloxy (e.g., phenoxy), aryl (e.g., phenyl), heteroaryl, heterocycloalkyl, amino, and keto. The term "lower heteroalkenyl" refers to heteroalkenyl groups having 3 to 6, preferably 3 to 4 atoms.

"heteroalkyl" refers to a monovalent saturated chain having from 2 to 18 member atoms (carbon and heteroatoms), preferably from 2 to 12, more preferably from 2 to 6 atoms in the chain. The heteroalkyl chain has at least one heteroatom. Heteroalkyl groups may be straight or branched. Preferred branched heteroalkyl groups have one or two branches, preferably one branch. The heteroalkyl chain may be unsubstituted or substituted with 1 to 4 substituents. Unless otherwise indicated, preferred heteroalkyl groups have 1 to 3 substituents. Substituents for heteroalkyl groups include aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkyl substituents include aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, halogen, hydroxy, amino, and keto groups. The term "lower heteroalkyl" refers to a heteroalkyl having from 2 to 6, preferably from 2 to 4, member atoms.

"heteroalkynyl" refers to a monovalent chain of 3 to 18 member atoms (carbon and heteroatoms), preferably 3 to 12, and more preferably 3 to 6 member atoms in the chain, and having at least one, and preferably only one, carbon-carbon triple bond. Heteroalkynyl chains have at least one heteroatom. Heteroalkynyl groups can be straight chain or branched. Preferred branched heteroalkynyl groups have one or two branches, preferably one branch. Heteroalkynyl groups can be unsubstituted or substituted with 1 to 4 substituents. Unless otherwise indicated, substituted heteroalkynyl groups preferably have 1 to 3 substituents. Heteroalkynyl substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, cycloalkyl, heterocycloalkyl, halogen, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heteroalkynyl substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, heterocycloalkyl, halogen, hydroxy, amino, and keto. The term "lower heteroalkynyl" refers to heteroalkynyl groups having 3 to 6, preferably 3 to 4, member atoms.

"heteroaryl" refers to an aromatic ring containing carbon atoms and 1 to 6 heteroatoms in the ring. Heteroaryl groups can be monocyclic or fused ring systems. Monocyclic heteroaryl rings contain 5 to 9 member atoms (carbon and heteroatoms), preferably 5 or 6 atoms. Polycyclic heteroaryl rings contain 8 to 17 member atoms, preferably 8 to 12 member atoms. Polycyclic heteroaryl rings include ring systems wherein at least one ring is heteroaryl (the second ring can be aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkyl). Preferred bicyclic heteroaryl ring systems include 5-, 6-, or 7-membered rings fused to a 5-, 6-, or 7-membered ring. Preferred heteroaryl rings include, but are not limited to, the following:

oxazolidine Isoxazole

Isothiazole thiazole 1, 2, 5-thiadiazole 1, 2, 3-triazole 1, 3, 4-thiadiazole furazan

1, 2, 3-thiadiazole 1, 2, 4-thiadiazole benzotriazole 1, 2, 4-triazole tetrazole

1, 2, 4-Oxadiazole 1, 3, 4-Oxadiazole 1, 2, 3, 4-thiatriazole 1, 2, 3, 5-thiatriazole

1, 2, 3, 5-Oxatrizole 1, 2, 3-triazine 1, 2, 4, 5-tetrazine biphenyl furan

Pyridinidazinopyrimidinylpyrazine 1, 3, 5-triazinindolizindoles

Isoindolylbenzofuran benzothiophene 1H-indazolpurine quinolines

Benzoxazole pteridine carbazole benzimidazole

Isoquinoline cinnoline phthalazine quinazoline quinoxaline 1, 8-naphthopyridine

Acridine phenazine

Heteroaryl rings may be unsubstituted or substituted on the ring with 1 to 4, preferably 1 to 3, more preferably 1 to 2 substituents. Preferred heteroaryl rings are unsubstituted or substituted with 1 or 2 substituents. Heteroaryl groups may be substituted with: halogen, cyano, nitro, hydroxy, amino, alkyl, lower alkenyl, lower alkynyl, heteroalkyl, aryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy, or any combination thereof. Preferred heteroaryl ring substituents include halogen, cyano, amino, alkyl, heteroalkylaryloxy, alkoxy, methylenedioxy, thioalkoxy, thioaryloxy.

"heteroatom" means a nitrogen, sulfur or oxygen atom. Groups containing more than one heteroatom may contain different kinds of heteroatoms.

"heterocycloalkyl" refers to a saturated ring containing carbon atoms and 1 to 4, preferably 1 to 3, heteroatoms in the ring. The heterocycloalkyl ring is not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged or spiro polycyclic ring systems. Monocyclic heterocycloalkyl rings contain 3 to 9 member atoms (carbon and heteroatoms), preferably 5 to 7 member atoms. Polycyclic heterocycloalkyl rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms. Preferred polycyclic heterocycloalkyl rings include 5-, 6-, or 7-membered rings fused to a 5-, 6-, or 7-membered ring. Preferred heterocycloalkyl rings include, but are not limited to, the following rings:

oxirane ethyleneimine oxetane chlorooxetane tetrahydrofuran pyrrolidine 3H-indole

1, 3-Dioxolane 1, 2-Dithiolane 1, 3-Dihydroisoxazole 4, 5-Dihydroisoxazole 2, 3-Dihydroisoxazole

4, 5-Diazopyrazolylimidazoline indoline 2H-pyrrole Phenoxazine 4H-quinoline

Pyrazolidine 2H-pyrane 3, 4-dihydro-2H-pyrane tetrahydropyran 2H-benzopyran

Chromone chroman piperidine morpholine 4H-1, 3-Oxazine 6H-1, 3-Oxazine

5, 6-dihydro-4H-1, 3-oxazine 4H-3, 1-benzokazine phenothiazine 1, 3-Dioxane

Cephalosporin piperazine hexahydroazepine 1, 3-dithiane 1, 4-Dioxane penicillin

Coumarin thiomorpholine uracil thymine cytosine thiacyclobutane

2, 3-dihydro-1H-isoindole-phthalic acid 1, 4-oxathiolane 1, 4-dithiane hexahydropyridazine

1, 2-benzisothiazoline benzyl sultam

The heterocycloalkyl ring may be unsubstituted or may be substituted on the ring with 1 to 4 substituents. Substituents for heterocycloalkyl include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), thioalkoxy, thioaryloxy, heteroaryl, cycloalkyl, halogen, hydroxy, amino, keto, thioketo, nitro, and cyano. Preferred heterocycloalkyl substituents include alkyl, aryl (e.g., phenyl), alkoxy, aryloxy (e.g., phenoxy), heteroaryl, halo, hydroxy, amino, and keto groups.

"keto" refers to an ═ O group.

"nitro" means-NO₂A group.

"optical isomers", "stereoisomers" and "s diastereomers" are used herein with standard technical identification (see, e.g., Hawley's Condensed Chemical Dictionary, 11 th edition). Derivatives of the compounds of the present invention are illustrated and not intended to be limiting. The use of effective protecting groups, salt forms, etc., is within the ability of the skilled artisan.

"pharmaceutically acceptable salt" refers to a cationic salt formed with any acidic group (e.g., carboxylic acid), or an anionic salt formed with any basic group (e.g., amino group). Many of these salts are known in the art, as described in world patent publication 87/05297(Johnston et al, published 9/11 1987), which is incorporated herein by reference. Preferred cationic salts include alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts), as well as organic salts. Preferred anionic salts include halides (e.g., chloride salts), sulfonates, carboxylates, phosphates, and the like. It is expressly intended that salts in which optical centers may be provided which were not present therein are included in the salts. For example, chiral tartrate salts may be prepared from the compounds of the present invention and are included in this definition.

Such salts are well known to the skilled person and the skilled person can prepare any amount of salt using the knowledge in the art. Furthermore, it is recognized that one salt may be preferred over another by the skilled artisan for reasons of solubility, stability, ease of formulation, etc. It is within the practice of the skilled person to determine and optimize these salts.

"Thioalkoxy" means-S (O)_0-2R groups, wherein R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, or heterocycloalkyl. Preferred thioalkoxy groups include methanesulfonyl.

"Thioaryloxy" means-S (O)_0-2R group, wherein R is aryl or heteroaryl. Preferred thioaryloxy groups include phenylsulfanyl, phenylsulfonyl and pyridylsulfonyl groups.

"thioxonyl" refers to the ═ S group.

Compound (I)

The present invention relates to compounds of formula (I):

(I)

in the above structure, each R¹Independently selected from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lower heteroalkenyl, lower heteroalkynyl, heterocycloalkyl, heteroaryl, halogen, CN, OR³、SR³、S(O)R³、S(O)₂R³And NR³R⁴. Preferably R¹Is lower alkyl, halogen, CN, OR³And NR³R⁴. More preferably R¹Lower alkyl, halogen and CN.

In the above structure, m is an integer of 0 to 5, preferably m is 0 to 3, more preferably m is 1 or 2.

In the above structure, Q is selected from:

andpreferably Q is

Each R²Independently selected from the group consisting of: H. alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, halogen, OH, CN, OR³、SR³、S(O)R³、S(O)₂R³And NR³R⁴. Preferably R²Are H and halogen. More preferably R²Is H.

X is selected from: CR²And N. Preferably X is CR². Most preferably, X is CH.

Y is selected from: CR²And N. Preferably, Y is CH or N.

Z is selected from CR²、NR³O and S.

In the above structure, a is selected from the following: zero, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³And S (O)₂R³. Preferably A is alkyl, alkynyl, aryl, heteroalkyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³、S(O)₂R³. More preferably, A is substituted alkyl (wherein the preferred substituents are keto, alkoxy, aryloxy, amino, heteroaryl, heterocycloalkyl) and aryl.

In the above structure, a is a single bond or a double bond, with the proviso that when a is zero, a is a double bond; when A is a group other than zero, a is a single bond.

In the above structure, B is selected from the following: zero, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³And S (O)₂R³. Preferably B is alkyl, alkynyl, aryl, heteroalkyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³、S(O)₂R³. More preferably B is substituted alkyl (wherein preferred substituents are keto, alkoxy, aryloxy, amino, heteroaryl, heterocycloalkyl) and aryl.

In the above structure, B is a single bond or a double bond, with the proviso that when B is zero, B is a double bond; when B is a group other than zero, B is a single bond.

In the above structure, one and only one of a and B is zero.

Each R³Independently selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl and heteroaryl. Preferably R³Is H, lower alkyl, heteroalkyl, aryl and heteroaryl.

Each R⁴Independently selected from H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, OR³And S (O)₂R³. Preferably R⁴Is H, lower alkyl and S (O)₂R³。

The invention also includes optical isomers, diastereomers and enantiomers of the above structures and pharmaceutically acceptable salts thereof.

While alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with hydroxy and amino groups as described above, the following are not contemplated by the present invention:

1. enols (OH attached to the carbon bearing the double bond).

2. An amino group attached to a carbon with a double bond (except for the vinylogous amide).

3. More than one (not containing one) hydroxyl, amino or amido group attached to one carbon (except where two nitrogen atoms are attached to one carbon atom and all three atoms are ring atoms in a heterocycloalkyl ring).

4. The hydroxy, amino or amido group is attached to a carbon atom which also carries a heteroatom.

5. The hydroxy, amino or amido group is attached to a carbon which also has a halogen attached.

Preparation of compounds

The compounds of the present invention can be prepared by conventional organic synthesis methods. It is particularly preferred that the synthesis be carried out according to the following general reaction schemes, schemes 1 and 2. Scheme 1 depicts a conventional reaction scheme for formulating compounds of the present invention when the "Q" substituent is a six-membered heterocyclic ring. Scheme 2 depicts a general reaction scheme for formulating compounds of the present invention when the "Q" substituent is a five-membered heterocycle.

Scheme 1

In scheme 1, R¹、R²、R³、R⁴M, X, Y, A, B and Q are as defined above. R' and R "will be defined below. The S1 a-type alkynes and S1 b-type substituted heterocycles are commercially available starting materials or can be prepared from commercially available starting materials by methods well known to those skilled in the art. The coupling of S1a and S1b to form the alkyne S1c was carried out using the method described by Mangaligiu, I. (Acta chem. Scand.1996, 50, 914-917). Alternatively, alkynes of the S1c type may be obtained from various commercially available substituted aryl halides and substituted 4-ethynyl-heterocycles, which in turn may be prepared by known methods. By known methods will3+2 cycloaddition of an S1c alkyne forms S1d triazole, but with slight changes in conditions, disubstituted triazoles can be obtained directly with sodium azide (see Caliendo et al, Eur. J. Med. chem.1999, 34, 719-one 727). Processing triazole type S1d under a variety of different conditions provides access to a variety of functionalized triazoles of types S1e and S1 f. For example, acylation of S1d with an acid halide and a tertiary amine base affords the amide. Reaction of S1d with an isocyanate or a tertiary carbamoyl chloride affords a urea. Alternatively, pretreatment of S1d with phosgene or a phosgene equivalent (e.g., triphosgene, carbonyldiimidazole) followed by contact with an amine will also yield a urea. Coupling of S1d with an arylboronic acid in a copper medium affords an arylamine. S1d is reacted with sulfuryl chloride and a tertiary amine base to give the sulfonamide.

R 'and R' are each a suitable functional group which enables the skilled person to functionalize the six-membered heterocyclic ring and ultimately form the compound of the invention. For further processing of the triazole backbone, R 'and R' on S1e can be replaced with various functional groups (R)²And NR³R⁴). In practice two methods are applied. In the first approach, a triazole of type S1d is substituted at the triazole nitrogen position as depicted in scheme 1 to give S1 e. When R 'or R' is-SMe, triazole S1e is specifically oxidized to the corresponding sulfoxide or sulfone (not shown) using several different common reagents (e.g., peracetic acid, 3-chloroperbenzoic acid, or potassium persulfate). The sulfoxide or the corresponding sulfone is then replaced under nucleophilic conditions with a compound of type S1 f. In the second method, S1d (where R 'and/or R' are-SMe) is first specifically oxidized to the sulfoxide or sulfone. The sulfoxide or sulfone then being nucleophilically substituted (with R)³By replacing R' and/or by R²Replacement of R "), followed by electrophilic substitution of the triazole ring as described previously, gives compounds of type S1 f. When either method is used, R 'and/or R' may be-SMe, halogen or some other such R²Or NR³R⁴A substituted substituent. Furthermore, the use of a halogen as R 'and/or R' prevents the additional step of oxidation of R 'and/or R' to a better leaving group.

Scheme 2

In scheme 2, R¹、R³、R⁴M, X, Y, A, B and Q are as previously defined. R 'and R' are as defined above. The alkynes of type S2a and the substituted heterocycles of type S2b are commercially available as starting materials or can be prepared from commercially available starting materials by methods well known to those of ordinary skill in the art. Several S2 b-type substituted heterocycles have been disclosed in the literature for a long time (Blass, B.E. et al, Bio.Med.chem.Lett.2000, 10, 1543-. The coupling of S2a and S2b to form an S2c type alkyne process was carried out as described in scheme 1. Alternatively, alkynes of the S2c type can be obtained from various commercially available substituted aryl halides and substituted 4-ethynyl-heterocycles, which can be prepared by sequential reactions using known methods. Oxidation of the sulfone by literature procedures followed by 3+2 cycloaddition with sodium azide as depicted in scheme 1 gives triazole S2 d. The resulting two heterocycles are functionalized to give the desired final compound as depicted in scheme 1.

In schemes 1 and 2, the steps can be varied to increase the yield of the desired product. One of ordinary skill in the art will recognize that the proper selection of reactants, solvents, and temperatures are important components of any successful synthesis. The determination of optimal conditions, solvents, reaction times and amounts is a routine procedure. Thus, the skilled person can use the guidance of the above schemes to synthesize different compounds.

It is to be appreciated that standard treatments of organic compounds can be readily performed by one of ordinary skill in the art of organic chemistry without further guidance; that is, it is well within the purview and practice of the ordinarily skilled artisan to perform such processing. These treatments include, but are not limited to: reduction of carbonyl compounds to their corresponding alcohols, oxidation of hydroxyl groups, etc., acylation, aromatic substitution, electrophilic and nucleophilic reactions, etherification, esterification and saponification, etc. Examples of such processes are discussed in standard textbooks such as March, Advanced organic chemistry (Wiley), Carey and Sundberg, Advanced organic chemistry (volume 2) and others, and are known to the skilled artisan.

When another potentially reactive molecular functionality is masked or protected, the skilled artisan can also readily determine which reaction is best performed, thereby avoiding unwanted side reactions and/or increasing the yield of the reaction. The ordinarily skilled artisan generally utilizes protecting groups to increase yield or to avoid undesirable reactions. These reactions can be found in the literature and are also within the scope of the skilled worker. Many examples of these treatments can be found, for example, in t. Of course, it is preferable to block the amino acid as a raw material having a reactive side chain to prevent the occurrence of an undesired side reaction.

The compounds of the invention may have one or more chiral centers. Thus, optical isomers, including enantiomers and diastereomers, can be selectively prepared relative to one another, for example, using chiral starting materials, catalysts, or solvents, or two stereoisomers or two optical isomers, including diastereomers and enantiomers (racemic mixtures) can be prepared simultaneously at once. Since the compounds of the present invention may exist in racemic form, mixtures of optical isomers including diastereomers and enantiomers may be separated by known methods, such as chiral salt methods, chiral chromatography, and the like.

In addition, it is known that an optical isomer, including diastereomers and enantiomers, or a stereoisomer, has many properties that are superior to those of other substances. Thus, when the present invention is disclosed and claimed, and a racemic mixture is disclosed, it is expressly intended that optical isomers (including diastereomers and enantiomers) or stereoisomers which are substantially free of each other are also disclosed and claimed.

Examples

The following non-limiting examples illustrateThe examples illustrate the compounds of the present invention and methods of preparing these compounds. If applicable, use¹H and¹³c NMR, elemental analysis, mass spectrometry and/or infrared spectroscopy.

All solvents purchased were of suitable grade and the reaction was carried out under inert nitrogen unless otherwise indicated. Chromatography was performed on silica gel (70 to 230 mesh; Aldrich) or (230 to 400 mesh; Merk), as applicable. Thin Layer Chromatography (TLC) was performed on a glass-backed silica gel plate (200 to 300 mesh; Baker) and developed with UV or 5% phosphomolybdic acid in ethanol (EtOH).

The following abbreviations are used herein:

MeOH: methanol Et₃N: triethylamine

EtOAc: ethyl acetate Et₂O: diethyl ether

Ph: phenyl conc: concentrated

DCE: 1, 2-dichloroethane TLC: thin layer chromatography

DMA: dimethylacetamide Ac: acetic acid salt

DMF: n, N-dimethylformamide h: hour(s)

d: day min: minute (min)

MCPBA: meta-chloroperbenzoic acid

LC/MS: liquid chromatography/Mass Spectrometry

prep hplc.: preparative scale high performance liquid chromatography

Example 1: 4- (4-fluorophenyl) -5- [2- (phenylmethylamino) pyrimidin-4-yl) -1-ethoxymethyl -[1，2，3]Triazole compounds

a)4- (4-fluorophenyl acetylene2-methylthiopyrimidine radical

Commercial 1-ethynyl-4-fluorobenzene and 4-chloro-2-thiomethylpyrimidine were reacted as described in Mangalagiu, I.et al (Acta chem. Scand.1996, 50, 914-917) to give the desired alkyne 1a as a brown solid. Many other alkyne intermediates can be made using essentially the same process, substituting the appropriate starting materials. The intermediates in Table 1 below were prepared according to the procedure just described substituting the appropriate starting materials.

TABLE 1

k)5- (4-fluorophenyl) -4- (2-methylthiopyrimidin-4-yl) -1-H- [1, 2, 3]Triazole compounds

To a stirred solution of alkyne 1a (11.8g, 48.3mmol) in DMA (500mL) was added sodium azide (3.14g, 48.3 mmol). The reaction mixture was heated to 80 ℃ and maintained for 2h until complete disappearance of 1a was indicated on TLC. The solution was diluted with aqueous buffer pH 6.4 and 1N HCl was added dropwise to restore the original acidic pH. The aqueous layer was extracted three times with ethyl acetate. With MgSO₄The combined organic layers were dried, filtered and concentrated to give a brown oil. In CH₂Cl₂Medium crystallization: hexane gives the desired product as a cream-colored solid.

1)4- (4-fluorophenyl) -5- (2-methylthiopyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]Triazole compounds And

5- (4-fluorophenyl) -4- (2-methylthiopyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]Triazole compounds

To a stirred solution of triazole 1k (638mg, 2.22mmol) in CH₂Cl₂To the solution (20mL) were added chloromethyl ether (227. mu.L, 2.44mmol) and triethylamine (340. mu.L, 2.44 mmol). The reaction was stirred at room temperature for 2h, or until TLC of the crude reaction mixture showed complete disappearance of 1 k. The solution was then diluted with 0.1N HCl and CH₂Cl₂Extraction was carried out three times. With MgSO₄The combined organic layers were dried, filtered and concentrated to dryness. The crude product was purified by preparative HPLC to give two separable positional isomers (approximately 1: 1) as a light yellow solid. Note that: the site selectivity depends on the reagents and reaction conditions.

m)4- (4-fluorophenyl) -5- (2-methylsulfinylpyrimidin-5-yl) -1-ethoxymethyl- [1, 2, 3] Triazole compounds

Stirring triazole 11(260mg, 0.753mmol) in CH₂Cl₂(3mL) the solution was cooled to 0 deg.C and MCPBA (130mg, 0.753mmol) in CH was added₂Cl₂(3mL) of the solution. The solution became turbid within a few minutes and the reaction was complete after 1.5h, as judged by TLC indication. The reaction mixture was then diluted with EtOAc and 0.5N Na₂S₂O₃Aqueous 10% NaHCO₃And brine washing. The remaining organic layer was MgSO₄Drying, filtering and concentrating to a dry state. The crude product was purified by preparative HPLC to give the desired product.

n)4- (4-fluorophenyl) -5- (2-methylsulfonylpyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]III Azole

Potassium persulfate (1.07g, 1.74mmol) in H at room temperature₂A solution of O (10mL) was added dropwise to a stirred solution of triazole 11(200mg, 0.58mmol) in MeOH (10 mL). The reaction was complete after 2h, which can be judged by analytical HPLC. The reaction mixture was concentrated to remove MeOH. The remaining aqueous solution was treated with 5% NaHCO₃Diluted and extracted twice with EtOAc. Mixing the organic layers with MgSO₄Drying, filtering and concentrating to a dry state. The crude product was used without further purification.

o)4- (4-fluorophenyl) -5- [2- (phenylmethylamino) pyrimidin-4-yl) -1-ethoxymethyl- [1，2，3]Triazole compounds

The solution of sulfoxide 1m () in benzylamine () was heated to c until 1e was completely lost as judged by LC/MS, typically requiring an overnight reaction. A short tube distillation head was attached to the top of the flask and the remaining amine was removed by distillation. The resulting crude product was then purified by preparative HPLC to give the desired product. Alternatively, product 1o can be prepared from sulfone 1n and benzylamine under similar conditions.

Examples 2 to 40 were prepared by essentially the same procedure as described in example 1, substituting the appropriate starting materials. The skilled person can vary the temperature, pressure, surrounding gas, solvent or reaction sequence as appropriate. In addition, the skilled person can suitably utilize protecting groups to prevent side reactions or to increase the yield. All such modifications can be readily made by those skilled in the art of organic chemistry and are intended to be within the scope of the present invention.

Examples 2 to 10 are illustrated by formula 7a and table 2 as follows:

TABLE 2

Examples 11 to 40 are illustrated by formula 7b and table 3 as follows:

TABLE 3

Example 41: 5- (4-chlorophenyl) -4- [2- (phenoxypyrimidin-4-yl) -1-ethoxymethyl- [1，2，3]Triazole compounds

a)5- (4-chlorophenyl) -4- (2-chloropyrimidin-4-yl) -1-H- [1, 2, 3]Triazole compounds

To a stirred DMA (120mL) solution of alkyne 1c (7.02g, 24.8mmol) was added sodium azide (1.61g, 24.8 mmol). The reaction mixture was heated to 80 ℃ for 2h until it was exhausted as judged by LC/MS. The solution was diluted with aqueous buffer pH 6.4 and 1N HCl was added dropwise to restore the original acidic pH. The aqueous layer was extracted three times with ethyl acetate. Mixing the organic layers with MgSO₄Dried, filtered and concentrated to give a brown oil which was used without purification.

h)4- (4-chlorophenyl) -5- (2-chloropyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]Triazole and 5- (4-chlorophenyl) -4- (2-chloropyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]Triazole compounds

To the CH of agitated triazole 41a (1.11gmg, 3.42mmol)₂Cl₂To the solution (20mL) were added chloromethyl ether (349. mu.L, 3.77mmol) and triethylamine (340. mu.L, 2.44 mmol). The reaction was stirred at room temperature for 2h, or until LC/MS indicated complete conversion of the crude reaction mixture. The solution was then diluted with 0.1N HCl and CH₂Cl₂Extraction was carried out three times. With MgSO₄The combined organic layers were dried, filtered and concentrated to dryness. The crude product was purified by preparative HPLC to give two separable positional isomers (approximately 1: 1) as a light yellow solid. Note that: the site selectivity depends on the reagents and reaction conditions.

c)5- (4-chlorophenyl) -4- (2-phenoxypyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3]Triazole compounds

To an agitated solution of benzylamine (290L, 2.7mmol) in tetrahydrofuran (4mL) was added sodium hydride (60% dispersion, 80mg, 2.0 mmol). After 5 minutes, the suspension was transferred by syringe to an agitated solution of chloropyrimidine 41b (233mg, 0.67mmol) in tetrahydrofuran (1 mL). The reaction mixture was stirred at room temperature overnight with H₂The solution was diluted with O and extracted three times with EtOAc. Mixing the organic layers with MgSO₄Drying, filtering and concentrating to a dry state. The crude product was purified by preparative HPLC to give the desired product.

Examples 42 to 52 were prepared by essentially the same procedure as described in example 41, substituting the appropriate starting materials. The skilled person can vary the temperature, pressure, surrounding gas, solvent or reaction sequence as appropriate. In addition, the skilled person can suitably utilize protecting groups to prevent side reactions or to increase the yield. All such modifications can be readily made by those skilled in the art of organic chemistry and are intended to be within the scope of the present invention.

Examples 42 to 52 are illustrated in Table 4 below:

TABLE 4

Example 53: (S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl]-1-benzene Radical- [1, 2, 3]Triazole compounds

a)4- (4-fluorophenyl) -5- (2-methylthio)Pyrimidin-4-yl) -1-phenyl- [1, 2, 3]Triazole compounds And

5- (4-fluorophenyl) -4- (2-methylthiopyrimidin-4-yl) -1-phenyl- [1, 2, 3]Triazole compounds

To an agitated triazole 1k (100mg, 0.35mmol) in CH₂Cl₂(6mL) to the solution was added phenylboronic acid (85mg, 0.70mmol), Cu (OAc)₂(95mg, 0.53mmol), pyridine (59. mu.L, 0.70mmol), and 4  molecular sieves (300 mg). The reaction was stirred for 72h and then filtered through a bed of celite. The filtrate was then concentrated to give the crude product, which was purified by preparative HPLC to give a separable mixture consisting of two positional isomers.

b)4- (4-fluorophenyl) -5- (2-methylsulfonylpyrimidin-4-yl) -1-phenyl- [1, 2, 3]Triazole compounds

The title compound was synthesized using the procedure described for the synthesis of compound 1 n.

c)4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl) -1-phenyl- [1, 2, 3] Triazole compounds

The title compound was synthesized using the procedure described for the synthesis of compound 1 o.

Examples 54 to 64 were prepared by essentially replacing the appropriate starting materials with the same procedures as described in example 53. The skilled person can vary the temperature, pressure, surrounding gas, solvent or reaction sequence as appropriate. In addition, the skilled person can suitably utilize protecting groups to prevent side reactions or to increase the yield. All such modifications can be readily made by those skilled in the art of organic chemistry and are intended to be within the scope of the present invention.

Examples 54 to 64 are illustrated by formula 7c and table 5 below:

TABLE 5

Example 65: 4- (4-fluorophenyl) -5- [ 3-methyl-2- (phenylmethylamino) -imidazol-4-yl]-1- Ethoxymethyl- [1, 2, 3]Triazole compounds

a)4- (4-fluorophenylethynyl) -3-methyl-2-phenylthioimidazole

The desired alkynes were obtained as brown oils by reacting fluorophenylacetylene with imidazole (Blass, B.E. et al, Bio.Med.chem.Lett.2000, 10, 1543-.

b)4- (4-Fluorophenylethynyl) -3-methyl-2-phenylsulfonylimidazole

To the stirred CH of alkyne 65a (2.70g, 8.7mmol)₂Cl₂To the solution (70mL) was added MCPBA (5.82g 70%, 20.7 mmol). After 24 h, the reaction was poured into 200mL EtOAc and washed with Na₂CO₃(3X 50mL) and MgSO 2₄Drying, filtering and separating to obtain solid. Hexane/EtOAc chromatography at 3/1 was used to produce alkyne 65b as a white solid.

c)4- (4-fluorophenyl) -5- [ 3-methyl-2-phenylsulfonylimidazol-4-yl]-[1，2，3]Triazole compounds

Alkyne 65b was reacted with sodium azide as described in example 1k to give the crude product as an oil. Chromatography with 1: 1 hexanes: EtOAc provided triazole 65c as a pale yellow solid.

d)4- (4-fluorophenyl) -5- [ 3-methyl-2-phenylsulfonylimidazol-4-yl]-1-ethoxymethyl- [1，2，3]Triazole and

5- (4-fluorophenyl) -4- [ 3-methyl-2-phenylsulfonylimidazol-4-yl]-1-ethoxymethyl- [1，2，3]Triazole compounds

The triazole 65c was reacted with chloroethoxymethyl ether as described in example 1l to give the crude product as an oil. Chromatography with 2: 1 hexanes: EtOAc provided the desired positional isomer as a pale white solid.

e)4- (4-fluorophenyl) -5- [ 3-methyl-2- (phenylmethylamino) -imidazol-4-yl]-1-ethoxymethyl Radical- [, 2, 3]Triazole compounds

The triazole 65d was reacted with benzylamine as described in example 1o to give the crude product as an oil. Chromatography with 60: 40: 0.8 hexanes, EtOAc, MeOH afforded 65e as a colorless oil.

Examples 66 to 70 were prepared by essentially the same procedure as described in example 65, substituting the appropriate starting materials. The skilled person can vary the temperature, pressure, surrounding gas, solvent or reaction sequence as appropriate. In addition, the skilled person can suitably utilize protecting groups to prevent side reactions or to increase the yield. All such modifications can be readily made by those skilled in the art of organic chemistry and are intended to be within the scope of the present invention.

Examples 66 to 70 are illustrated in Table 6 below:

TABLE 6

Application method

As mentioned above, the compounds of the present invention are potent cytokine inhibitors. In addition, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of diseases caused by excessive cytokine activity in humans or mammals.

The term "cytokine" as used herein refers to any secreted protein secreted by many different types of cells involved in intercellular communication that modulates interactions between cells in an inflammatory, immune or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), alpha and beta tumor necrosis factor, collectively referred to herein as (TNF), interleukin-8 (IL-8), and interleukin-6 (IL-6).

"cytokine inhibitor" as described herein refers to: (i) reducing excessive cytokine levels in vivo (such as but not limited to IL-1, TNF, IL-6 and IL-8) to normal or subnormal levels by inhibiting cytokine release by all cells in vivo; (ii) down-regulating excessive cytokine mRNA expression in humans to normal or subnormal levels; (iii) by inhibiting the direct synthesis of cytokines (such as but not limited to IL-1, TNF, IL-6 and IL-8), down-regulated as a post-translational event; or (iv) down-regulating excessive cytokine levels in humans to normal or below normal levels at the expression level.

The compounds of formula (I) may inhibit cytokines such as, but not limited to, IL-1, TNF, IL-6 and IL-8. These cytokines, as well as many other cytokines, are important initiators of inflammation in a variety of diseases. Inhibition of these inflammatory cytokines is beneficial in the treatment of these conditions. The invention also provides methods of treating diseases caused by proteases, wherein the production of the protease is affected by cytokines. Examples of such proteases include, but are not limited to, matrix metalloproteinases and disintegrated metalloproteinases (ADAMs).

The ability of compounds of formula (I) to inhibit TNF- α production was measured by the stimulation of human monocytes (THP-1) with Lipopolysaccharide (LPS) (see (a) Mohler K.M. et al, "prevention of accumulation of lethal doses of endotoxin by inhibition of tumor necrosis factor processing," Nature 1994, 370, 218-. Test compounds were incubated with THP-1 cells at various concentrations for 15 minutes before LPS (2go/mL) was added to stimulate cytokine release. The amount of TNF-. alpha.released was measured after 4 hours using a commercially available ELISA tool. The inhibition of TNF-alpha release by the test compounds was determined by comparison with LPS-treated cultures without test compounds.

A compound of formula (I) is administered in an amount sufficient to inhibit cytokines such as, but not limited to, IL-1, TNF, IL-6, and IL-8, to control them at normal levels or below, thereby preventing disease. In the present invention, it is considered that the amount of cytokine is abnormal, composition; free cytokines (such as, but not limited to, IL-1, TNF, IL-6, and IL-8) in an amount greater than or equal to 1 picogram/ml; any cytokine-binding cell or; the cytokine mRNA is present in the cell or tissue in an amount greater than the basal level.

Thus, these compounds are effective therapeutic agents for the treatment of diseases associated with unwanted cytokine activity, these diseases include osteoarthritis, rheumatoid arthritis, septic arthritis, psoriatic arthritis, rheumatic fever, gout, reiter's syndrome, osteoporosis, diabetes, inflammatory bowel diseases including crohn's disease and ulcerative colitis, pancreatitis, diverticulitis, sepsis, septic shock, toxic shock syndrome, respiratory diseases including asthma, Chronic Obstructive Pulmonary Disease (COPD), bronchitis, emphysema, cystic fibrosis, acute dyspnea, pulmonary and hepatic fibrotic diseases, central nervous system diseases such as alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), muscular dystrophy and multiple sclerosis, cachexia secondary infection or malignant and cachexia secondary acquired immune deficiency syndrome.

Since cytokines can lead to excessive proteases, the compounds of the present invention are effective in inhibiting prosthesis relaxation. It is well known in the art that loosening of the prosthesis can become painful over time and can cause further bone injury, thus requiring replacement. Such prostheses that require replacement include those such as joint replacements (e.g., hip, knee and shoulder prosthesis replacements), dental prostheses, including brackets, bridges and prostheses that secure the maxilla and/or mandible.

Cytokines and proteases are also active in the remodeling of the cardiovascular system. It has been proposed that one of the causes of angioplasty having a higher than expected rate of prolonged failure (reclosing over time) is the undesirable activity of cytokines and proteases, or its rise in response to what the body recognizes as "damage" to the vascular basement membrane. Similarly, re-narrowing of surgical cardiovascular stents is thought to be due to cytokine-induced protease production in response to "damage" caused by insertion of the stent's fixation membrane.

The compounds of the present invention are also useful in the treatment of diseases caused by excessive or inappropriate angiogenesis. Such diseases, conditions or disorders include, but are not limited to, various eye diseases such as macular degeneration and diabetic retinopathy, tumor growth and metastasis, atherosclerosis and rheumatoid arthritis.

For skin care, cytokines imply remodeling and "turnover" of the skin. Thus, modulation of cytokines facilitates treatment of skin conditions including, but not limited to, wrinkle repair, regulation, prevention and repair of ultraviolet-induced skin damage. Such treatment includes prophylactic treatment or treatment before the manifestation of the physiological symptoms are evident. For example, cytokine inhibitors may be used as a prophylactic treatment to prevent ultraviolet damage and/or to prevent or minimize damage caused after irradiation during or after irradiation. In addition, cytokines are involved in skin disorders and diseases associated with abnormal tissue resulting from abnormal turnover such as epidermal laxity blistering, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention can also be used to treat symptoms caused by "normal" damage to the skin, including, for example, "atrophy" of scars or tissue caused by burns and possibly by hair growth regulation.

It is also believed that cytokine inhibition can be used to treat ophthalmic diseases (especially corneal ulcers, corneal healing defects, macular degeneration and pterygium), gum diseases (especially periodontal disease and gingivitis). Preferably, but not limited to, compounds for the treatment of ophthalmic, dental and dermatological disorders may be administered topically.

Composition comprising a metal oxide and a metal oxide

The composition of the present invention comprises:

(a) a safe and effective amount of a compound of the present invention; and

(b) a pharmaceutically acceptable carrier.

As described above, many diseases are known to be caused by excessive or undesirable cytokine activity. For example, such diseases include osteoarthritis, rheumatoid arthritis, diabetes, HIV/aids, inflammatory bowel disease, chronic heart failure, hypertension, periodontitis, and the like. Thus, the compounds of the present invention are useful in the treatment and prevention of conditions that include such undesirable activity.

Accordingly, the compounds of the present invention may be formulated into pharmaceutical compositions for the treatment or prevention of these diseases. Standard pharmaceutical preparation techniques may be employed, such as those disclosed in Remington's pharmaceutical sciences, Mack publishing company, Easton, Pa. latest edition.

A "safe and effective amount" of a compound of formula (I) is an amount that is effective at inhibiting a cytokine in an animal, preferably a mammal, more preferably a human, at the active site without adverse effects (e.g., toxicity, irritation, or allergic response) and at a reasonable benefit/risk ratio when used in the manner of this invention. It will be apparent that the specific "safe and effective amount" will vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the performance of the current therapy (if any), the specific dosage form employed, the carrier employed, the solubility of the compound of formula (I) of the present invention, and the desired dosage regimen of the present composition.

In addition to the compounds of the invention, the compositions of the invention also contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid filler diluents or capsule materials suitable for administration to an animal, preferably a mammal, more preferably a human. The term "compatible" as used herein means that the components of the composition are capable of being mixed with the compounds of the present invention and do not interact with each other in ordinary use to substantially reduce the pharmaceutical efficacy of the composition. Of course, the pharmaceutically acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to an animal, preferably a mammal, more preferably a human, in need of treatment.

Examples of substances that can be used as pharmaceutically acceptable carriers or components thereof include sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered gum tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, e.g. Tweens^(ii) a Wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tablets, stabilizers; an antioxidant; a preservative; no heat source water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically acceptable carrier to be used with the present compounds will depend essentially on the mode of administration of the compound.

If the present compounds are to be injected, the preferred pharmaceutically acceptable carrier is sterile physiological saline with a hemocompatible suspending agent adjusted to a pH of about 7.4.

In particular, pharmaceutically acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water. Preferred parenteral vehicles include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable carrier for parenteral administration in the composition is at least about 90% by weight of the total composition.

The compositions of the present invention are preferably provided in unit dosage form. The term "unit dosage form" as used herein refers to compositions of the present invention containing a compound of formula (I) suitable for single dose administration to an animal, preferably a mammal, more preferably a human patient, in accordance with good medical practice. These compositions preferably comprise from about 5mg to about 1000mg, more preferably from about 10mg to about 500mg, more preferably from about 10mg to about 300mg of the compound of formula (I).

The compositions of the invention may be in various forms, for example suitable for oral, rectal, topical, nasal, ocular or parenteral administration. Depending on the desired route of administration, various pharmaceutically acceptable carriers known in the art may be used including solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating materials. An optional pharmaceutically acceptable active agent may be included, provided that it does not substantially interfere with the inhibitory activity of the compound of formula (I). The amount of carrier used in conjunction with the compound of formula (I) should be sufficient to provide a practical amount of material for administration per unit dose of the compound of formula (I). Techniques and compositions for preparing dosage forms suitable for use in the methods of the present invention are described in the following references, all of which are incorporated herein by reference: modern medicine (Modern pharmaceuticals), chapters 9 and 10, (Banker and Rhodes, eds., 1979); lieberman et al, pharmaceutical dosage forms: tablets (1981); and Ansel, pharmaceutical dosage form introduction, 2 nd edition (1976).

Various oral dosage forms may be used, including solid dosage forms such as tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of a compound of formula (I), typically at least about 5%, preferably from about 25% to about 50%. Tablets may be compressed, ground, enteric-coated, sugar-coated, film-coated or multi-layered compressed tablets containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, drainage agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions made from non-effervescent granules, and effervescent formulations made from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and flavoring agents.

Pharmaceutically acceptable carriers suitable for preparing unit dose oral administration forms are well known in the art. Tablets typically comprise as inert diluents conventional adjuvants compatible with the drug, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrating agents such as starch, alginic acid and croscarmelose; lubricants, for example, magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide may be used to improve the flowability of the powder composition. Colorants such as FD & C dyes may be added to beautify the appearance. Sweetening agents and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are suitable adjuvants for chewable tablets. Capsules typically include one or more of the solid diluents disclosed above. The second consideration in selecting carrier components is taste, price and shelf stability, which are not critical to the objects of the present invention and which can be readily accomplished by one skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose RC-591, gum tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more of the above disclosed components, such as sweetening, flavoring, and coloring agents.

These compositions may also be coated by conventional means, typically using a pH or time dependent coating, so that the compounds of the invention are released in the gastrointestinal tract adjacent to the desired topical application, or at different times to prolong the desired duration of action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, cellulose polyacetate phthalate, hydroxypropylmethylcellulose, cellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

The compositions of the present invention may optionally include other pharmaceutically active substances.

Other compositions suitable for delivery of the compounds of the present invention include sublingual, buccal and nasal dosage forms. These compositions typically contain one or more soluble bulking agent materials, such as sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

The compositions of the present invention may also typically be administered by, for example, applying or spraying the composition directly onto the epidermis or epithelial tissue of the patient, or transdermally via a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, generally at least about 0.1%, preferably from about 1% to about 5%, of a compound of formula (I). Suitable topical carriers preferably remain on the skin as a continuous film and are not easily removed by perspiration or immersion in water. Typically, the carrier herein is organic in nature and is capable of dispersing or dissolving the compound of formula (I). The carrier may include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents and the like.

Mode of administration

The present invention also provides methods for treating or preventing disorders due to excessive or undesirable cytokine activity in a human or other animal patient by administering to the user a safe and effective amount of a compound of formula (I). The methods of the invention can be used to treat or prevent the above disorders.

The compositions of the present invention may be administered both topically and systemically. Systemic applications include any method of introducing a compound of formula (I) into body tissues, such as intra-nodal-articular (particularly in the treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, intrarectal and buccal administration. The compounds of formula (I) of the present invention are preferably administered orally.

The particular inhibitor administered dose and duration of treatment, and whether local or systemic treatment is interdependent. The dosage and treatment regimen will also depend on such factors as the particular compound of formula (I) used, the therapeutic index, the ability of the compound of formula (I) to achieve a minimum inhibitory concentration at the site of metalloprotease inhibition, the user's attributes (e.g., body weight), the compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.

Typically, for adults (weighing about 70 kg), from about 5mg to about 3000mg, more preferably from about 5mg to about 1000mg, more preferably from about 10mg to about 100mg of a compound of formula (I) are administered per day for systemic administration. It is understood that these dosage ranges are for illustration only and that the daily dosage amount can be adjusted based on the factors described above.

The preferred method of administration for the treatment of rheumatoid arthritis is oral or parenteral intra-nodal-articular injection. All formulations for parenteral administration must be sterile, as is known in the art and practiced in the art. For mammals, especially humans (assuming a body weight of about 70 kg), a preferred individual dose is from about 10mg to about 1000 mg.

The preferred method of systemic administration is oral. Preferably, each dose is from about 10mg to about 1000mg, preferably from about 10mg to about 300 mg.

The compounds of formula (I) may be delivered systemically using topical administration, or to treat a localized area. The amount of the compound of formula (I) administered topically will depend on such factors as the sensitivity of the skin, the type and location of the tissue to be treated, the composition and carrier (if present) to be administered, the particular compound of formula (I) administered, and the nature of the condition to be treated and the extent of systemic (as distinguished from site-directed) effect desired.

The inhibitors of the invention may be directed to specific sites where cytokines are accumulated by the target ligand. For example, to focus inhibitors on cytokines contained in a particular type of cell, the inhibitor may be conjugated to an antibody or antibody fragment that immunoreacts with a cellular marker, as is generally understood in the preparation of immunotoxins. The target ligand may also be a ligand for a receptor present on the target cell. Any target ligand that specifically reacts with the marker for a given target tissue may be used. Methods for coupling the compounds of the invention with the target ligand are well known and are similar to those described below for coupling with a support. The conjugates can be prepared and administered as described above.

For local symptoms, topical administration is preferred. For example, to treat an ulcerated cornea, an eye drop or aerosol formulation can be applied directly to the affected eye. For treatment of the cornea, the compounds of the invention may also be formulated as a gel, drop or ointment, or incorporated into a collagen or hydrophilic polymer shell. The substance may also be inserted as a contact lens or reservoir or as a conjunctival formulation. For the treatment of skin inflammation, the present compounds may be included in gels, pastes, ointments or salves for topical or local application. For the treatment of oral diseases, the compounds can be included in gels, pastes, mouth washes or implants for site-directed application. Thus, the nature of the treatment regimen in response to the symptoms, and the formulation available in the art for any selected regimen.

Of course, in all of the foregoing descriptions, the compounds of the present invention may be administered alone or in admixture, as required by the indication, and the composition may also include additional drugs or excipients.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. A compound having the structure of formula (I):

wherein,

a. each R¹Independently selected from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower heteroalkyl, lower heteroalkenyl, lower heteroalkynyl, heterocycloalkyl, heteroaryl, halogen, CN, OR³、SR³、S(O)R³、S(O)₂R³And NR³R⁴；

b.m is an integer from 0 to 5;

c.Q is selected from

And

d. each R²Independently selected from the group consisting of: H. alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, halogen, OH, CN, OR³、SR³、S(O)R³、S(O)₂R³And NR and³R⁴；

e.X is selected from: CR²And N;

f.Y is selected from: CR²And N;

g.Z is selected from CR²、NR³O, and S;

h. a is selected from the following substances: zero, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³And S (O)₂R³；

A is a single or double bond, with the proviso that when a is zero, a is a double bond; when A is a group other than zero, a is a single bond;

j.B is selected from the following: zero, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heteroaryl, OR³And S (O)₂R³；

k.b is a single or double bond, with the proviso that when B is zero, B is a double bond; when B is a group other than zero, B is a single bond;

1. provided that one and only one of A and B is zero;

m. each R³Independently selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl and heteroaryl;

n. each R⁴Independently selected from H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenylaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, OR³And S (O)₂R³；

Or an optical isomer, diastereomer or enantiomer of formula (I), or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Q is

3. A compound according to one of claims 1 or 2, wherein R¹Selected from the group consisting of lower alkyl, CN, and halogen.

4. A compound according to any one of claims 1 to 3, wherein a or B is selected from the following: alkyl, cycloalkyl, aryl, heteroalkyl, heterocycloalkyl, heteroaryl, OR³And S (O)₂R³。

5. The compound of any one of claims 1 to 4, wherein A or B is selected from the group consisting of: alkyl, aryl, heteroalkyl, and heterocycloalkyl.

6. The compound of any one of claims 1 to 5, wherein A is zero.

7. The compound of any one of claims 1 to 6, wherein each R¹Independently selected from: F. CL, CF₃CN, and CH₃。

8. A compound selected from the group consisting of:

4- (4-fluorophenyl) -5- [2- (phenylmethylamino) pyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [ 2-aminopyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (methylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (isopropylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (phenylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (4-methylphenylmethylamino) -pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (4-methoxyphenylmethylamino) -pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (4-fluorophenylmethylamino) -pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (S) -phenylethylamino) -pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-methylcarbonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (furan-2-ylcarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-phenylcarbonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (4-methoxyphenylcarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (4-chlorophenylcarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-ethoxycarbonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (phenylthio-thiocarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-phenylmethoxycarbonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2-methoxyethoxycarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-methoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- [ (2-methoxyethoxy) -methyl ] - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (phenylmethoxymethyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2-methoxyethyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2-ethoxyethyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2-phenoxyethyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-methylsulfonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1-phenylsulfonyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2-furansulfonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (N-ethyl-N-phenylaminocarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (2, 3, dihydro-indol-1-ylcarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (N, N-dimethylaminocarbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (tetrahydrofuranyl-N-carbonyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (R) -phenylethylamino) -pyrimidin-4-yl ] -1- (morpholinyl-N-carbonyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (piperidinyl-N-carbonyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (tetrahydrofuran-4-ylcarbonyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (pyrrol-2-ylcarbonyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (pyrrol-3-ylcarbonyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (tetrahydrofuran-4-yl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (tetrahydrofuran-4-ylmethyl) - [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl ] -1- (2-aminoethyl) - [1, 2, 3] triazole

5- (4-chlorophenyl) -4- [ 2-phenoxypyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole 4- (4-chlorophenyl) -5- [2- (phenylmethylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

5- (4-chlorophenyl) -4- [2- (phenylmethylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (3-trifluoromethylphenyl) -5- [2- (phenylmethylamino) pyrimidin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -5- (4-fluorophenyl) -4- [2- (1-phenylethylamino) -pyridin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyridin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -5- [3- (trifluoromethyl) phenyl ] -4- [2- (1-phenylethylamino) -pyridin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -4- [3- (trifluoromethyl) phenyl ] -5- [2- (1-phenylethylamino) -pyridin-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [4- (1-phenylethylamino) -pyrimidin-6-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [ 2-chloro-4- (1-phenylethylamino) -triazin-6-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- (2-aminopyridin-4-yl) -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- (2-aminopyrimidin-4-yl) -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (4-methylphenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (4-methoxyphenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (3, 4-dimethoxyphenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- ([1, 3] benzodioxol-5-yl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- [4- (2-methoxyethoxy) -phenyl ] - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (4-phenoxyphenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- [4- (N, N-dimethylamino) -phenyl ] - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (4-chlorophenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (3-fluorophenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- (4-methylsulfinylphenyl) - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (1-phenylethylamino) -pyrimidin-4-yl-1- [4- (methoxycarbonyl) -phenyl ] - [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [ 3-methyl-2- (phenylmethylamino) -imidazol-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

5- (4-fluorophenyl) -4- [ 3-methyl-2- (phenylmethylamino) -imidazol-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(R) -4- (4-fluorophenyl) -5- [ 3-methyl-2- (1-phenylethylamino) -imidazol-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

(S) -4- (4-fluorophenyl) -5- [ 3-methyl-2- (1-phenylethylamino) -imidazol-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (phenylmethylamino) -imidazol-4-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

4- (4-fluorophenyl) -5- [2- (phenylmethylamino) -oxazol-5-yl ] -1-ethoxymethyl- [1, 2, 3] triazole

9. A pharmaceutical composition comprising:

(a) a safe and effective amount of a compound of any one of claims 1 to 8; and

(b) a pharmaceutically acceptable carrier.

10. A method for preventing or treating a disease associated with unwanted cytokine activity in a mammal, comprising administering to said patient a safe and effective amount of a compound as claimed in any one of claims 1 to 8.

11. The method of claim 10, wherein the condition is osteoarthritis.

12. The method of claim 10, wherein the disorder is rheumatoid arthritis.

13. The method of claim 10, wherein the condition is congestive heart failure.